Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review Authors: Catarino, Rosa; Costa, Flávio; Félix, Joana; Leal, Nuno; Mendes, Leonor;

Polymorphisms of Inflammatory Genes and Gastric Cancer: A

Systematic Review

Authors: Catarino, Rosa; Costa, Flávio; Félix, Joana; Leal, Nuno; Mendes, Leonor; Moreira, Helena; Peixoto, Carla; Sampaio, Maria; Santos, Joana; Sequeira, Ana; Sousa, Joel; Tavares, Maria.

Supervisors:

Mário Dinis-Ribeiro,

Altamiro da Costa-Pereira

Introduction to Medicine 2006/2007

http://www.nlm.nih.gov/

Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

2

Stomach cancer incidence Stomach cancer incidence ratesrates

- By sex (Europe)

http://health.gov.mt/ministry/dhi/publications/mncr/stomach.htm


3

Stomach cancer Survival Stomach cancer Survival ratesrates

Stomach cancer - five year survival

*standardised relative survival for stomach cancer by sex for patients diagnosed in England and Wales during 1971-1999

http://info.cancerresearchuk.org


4

CancerCancerDisease in which the body's cells become abnormal and divide

without control.Cancer cells may invade nearby tissues and they may spread

through the bloodstream and lymphatic system to other parts of the body.

Stomach CancerStomach CancerStomach cancer is the growth of cancer cells in the lining and wall

of the stomach.Stomach cancers are believed to develop slowly over many years.

MEN / WOMEN ENVIRONMENT

Polymorphisms of Inflammatory Genes Gastric Cancer

http://www.cancer.gov/cancerinfo/wyntk/stomachhttp://www.nlm.nih.gov/medlineplus/stomachcancer.html

Risk factor?

Protective factor?


5

Epidemiological studies show a clear association between chronic inflammatory conditions and subsequent malignant transformation in the inflamed tissue.

Polymorphisms of Inflammatory Polymorphisms of Inflammatory Genes as a gastric cancer’s Genes as a gastric cancer’s causecause

Chronic inflammation is characterized by infiltration of damaged tissue by mononuclear cells together with tissue destruction and attempts at repair.

A cardinal feature of inflamed tissues is the generation of NO and the presence of an inducible enzyme with carcinogenic properties – Cyclooxygenase-2 (COX-2)

Among the most potent inducers of COX-2 are the key proinflammatory cytokines IL-1 and TNF.NO, its products, and COX-2 may exert oncogenic effects via several mechanisms

http://www.nlm.nih.gov/


6

Proinflammatory cytokine gene polymorphisms may increase or reduce the risk of cancer and its precursors.

Polymorphisms of Inflammatory Polymorphisms of Inflammatory Genes as a gastric cancer’s Genes as a gastric cancer’s causecause

IL-1IL-1ββ, IL-6, TNF-TNF-αα, CXCL,

CCR, COX-2COX-2

Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003

Genetic polymorphisms directly influence interindividual variation in the magnitude of cytokine response, and this clearly contributes to an individual’s ultimate clinical outcome.


7

Aim:Aim:

To perform a systematic review of studies on risk of gastric To perform a systematic review of studies on risk of gastric cancer associated with genetic polymorphisms related with cancer associated with genetic polymorphisms related with Cox, TNF and IL-1.Cox, TNF and IL-1.


8

MethodsMethods


9

StudyStudy designdesign

We conducted an exhaustive search for primary studies in a general database – Medline, using the following query:

((risk*[Title/Abstract] OR risk*[MeSH:noexp] OR risk *[MeSH:noexp] OR cohort studies[MeSH Terms] OR group*[Text Word]) OR (incidence[MeSH:noexp] OR mortality[MeSH Terms] OR follow up studies[MeSH:noexp] OR prognos*[Text Word] OR predict*[Text Word] OR course*[Text Word]))

AND((("Polymorphism, Single Nucleotide"[MeSH] OR "Polymorphism, Genetic"[MeSH]) OR polymorphism) AND (("Cyclooxygenase 2"[MeSH] OR "Cyclooxygenase 1"[MeSH]) OR ("Interleukin-1"[MeSH] OR "Receptors,

Interleukin-1"[MeSH]) OR "Tumor Necrosis Factor-alpha"[MeSH] OR Cox OR IL-1 OR TNF) AND ("Stomach"[MeSH] OR "Stomach Neoplasms"[MeSH] OR gastric) AND (cancer OR adenocarcinoma))

We have found 86 potential studies.


10

• Inclusion Criteria:Inclusion Criteria:

Original articles, observational studies, that evaluated the risk of gastric cancer according to Polymorphisms of Inflammatory Genes

• Exclusion Criteria:Exclusion Criteria:

Case Reports Case series Reviews Language (we only accept articles written in English

or French)

Study designStudy design


11

Flow Chart – First StageFlow Chart – First StageStart

NoYes

Fullfil the inclusion criteria?

Yes

No

32 articles excluded

Read titles and abstractsN=48

3 articles had no abstract

Read titles and abstractsN=83

Obtain full articlesN=3

Read full articlesN=3

Identify adequate databases

Perform bibliographic research on MedLine

Define a Query

48 articles included

I ncluded by two reviewers?

Read by a third reviewer

Include article?

Yes

No

35 abstracts excluded

(Not related with the theme)


Search for full articles in MedLine and Scopus

19 articles found

86 articles found


12

Flow Chart – Second StageFlow Chart – Second Stage19 articles found

Select full articles according to inclusion and exclusion criteria

I ncluded by two reviewers?

Read by a third reviewer

Yes No

Include article?

Yes


No

4 articles excluded

Extract Data(2 reviewers)

I nsert and analyse data using SPSS and RevMan

Discuss and interprete the results

Identify limitations of the review

Write the report

End


13

ResultsResults


14

SELECTION BIASSELECTION BIAS1. Did the investigators do any type of blinding?2.Did the investigators demonstrate similarity in all known determinants of outcome?3. Did they adjust for differences in the analysis?

PERFORMANCE BIASPERFORMANCE BIAS4. Were persons responsible for assessing outcome unware of the assigned intervention? 5. Were exposed patients equally likely to be identified in the two groups?

ATTRITION BIASATTRITION BIAS6. Was follow up sufficiently complete (at least

80%)?

DETECTION BIASDETECTION BIAS7. Were the outcomes measured in the same way in the groups being compared?

Quality criteriaQuality criteria


15

AuthorType of Study

Blinding of

outcome

assesors

Elimination of

confounders

Adjustment for

differences

Unawareness of the assigned

intervention

Identifica-tion of the groups

Follow-up

complete

Similarity in

measuring the

outcomes

Pereira C.

CC Y Y Y Y Y - Y

Ikehara SK.

CC Y N N N Y - Y

Starzynska T.

CC Y Y Y Y Y - Y

Hellmig S. CC Y Y Y Y Y - Y

Palli D. CC Y Y Y Y Y - Y

Perri F. CC Y N N N Y - Y

Zhang WH.

CC Y N N Y Y - Y

Lu W. CC Y Y Y Y Y - Y

Chang YW. CC Y Y Y Y Y - Y

Hartland S. CC Y Y Y Y Y - Y

Zeng ZR. C Y Y Y Y Y U Y

El-Omar EM. CC Y N N Y Y - Y

Figueiredo C. CC Y Y Y Y Y - N

Machado JC.

CC Y Y Y Y Y - Y

El-Omar EM. CC Y Y Y Y Y - Y

Y - Yes

N - No U - Unknown

Quality analysisQuality analysis

CC- Case-control

C - Cohort


16

Quality analysisQuality analysis

Quality Criteria

012345678

Ikeh

ara

SK

.

El-O

mar

EM

.

Fig

ueire

doC

.

Sta

rzyn

ska

T.

Pal

li D

.

Cha

ng Y

W.

Mac

hado

JC.

Zen

g Z

R.

Articles

Qu

alit

y


17

Studies characteristicsStudies characteristics

Case-controlsCase-controls

Pereira C., 2006Pereira C., 2006

Ikehara SK., 2006Ikehara SK., 2006

Starzynska T., Starzynska T., 20062006

Hellmig S., 2005Hellmig S., 2005

Palli D., 2005 Palli D., 2005

Perri F., 2005Perri F., 2005 Zhang WH., 2005Zhang WH., 2005

Lu W., 2005Lu W., 2005

PolymorphiPolymorphismsm

COX-2COX-2

IL-1B-31,-511IL-1B-31,-511

IL-1B-511IL-1B-511

TNF-alfa-238, TNF-alfa-238, 308, 857, 308, 857, 10311031

IL-1B-31, IL-1B-31, +3954, -511+3954, -511

TNF-alfa-308TNF-alfa-308

IL-1B-31, -IL-1B-31, -511,511, +3954+3954

IL-1B-31, 511IL-1B-31, 511TNF-alfa-308TNF-alfa-308

Local Local of of StudyStudyPortugaPortugall

JapanJapan

PolandPoland

GermanGermanyy

Italy Italy

ItalyItaly

ChinaChina

ChinaChina

% male % male gendergender(cases)(cases)4949

7373

6161

5454

5858

6060

8484

7373

% male % male gendergender(controls)(controls)6464

7373

4848

4848

4949

5353

8484

7272


18

Case-controlsCase-controls

Chang YW., 2005Chang YW., 2005

Hartland S., 2005Hartland S., 2005 El-Omar EM., 2003El-Omar EM., 2003

Figueiredo C., Figueiredo C., 20022002 Machado JC., 2001Machado JC., 2001

El-Omar EM., 2000El-Omar EM., 2000 CohortsCohorts

Zeng ZR., 2003Zeng ZR., 2003

PolymorphisPolymorphismm

IL-1B-511, 31IL-1B-511, 31

IL-1B+3954, IL-1B+3954, 511511

IL-1B-511IL-1B-511TNF-alfa-308TNF-alfa-308

IL-1B-511IL-1B-511

IL-1B-511IL-1B-511

IL-1B-31, 511, IL-1B-31, 511, +3954+3954

IL-1B-511, 31, IL-1B-511, 31, +3954+3954

Local ofLocal of studystudy

S KoreaS Korea

UKUK

U.S.A.U.S.A.

PortugalPortugal

PortugalPortugal

U.S.A.U.S.A.

ChinaChina

% male % male gendergender(controls(controls))--

6868

7878

--

--

--

5858

% % male male gendegenderr(cases)(cases) --

3232

8585

--

--

--

3737



19



20

Pooled Pooled statisticsstatistics

IL-1 polymorphisms

Comparison: Gastric Cancer IL-1: Normal Vs Cancer

Outcome: Non carriers Vs Carriers

Forest Plot obtained by Revman software


21




22

Funnel Plot obtained by Revman software

Funnel Plot



23

Outcome: Homozygous dominant allele carriers vs Homozygous variant allele carriers

Pooled statistics



24

TNF-alfa polimorphism

Comparison: Gastric Cancer TNF-alfa: Normal Vs Cancer Outcome: Non carriers Vs Carriers


Pooled statistics

Outcome: Homozygous dominant allele carriers vs Homozygous variant allele carriers



25

ConclusionConclusion

Although some individual studies did not achieve statistically significant results, our pooled measures showed a relation between polymorphisms and gastric cancer.

This fact attests the importance of meta-analysis as a method of analyzing a great number of patients and compiling results from different and small studies.

The lack of significant outcomes may be explained by the small number of cohort studies.


26

ConclusionConclusion

• Based on our studies about TNF-alfaTNF-alfa we concluded that being a carrier or homozygous for this polymorphism may offer a protective effect against stomach cancer.

• For the IL-1B-31 IL-1B-31 polymorphism, being a carrier or homozygous means having increased risk for cancer.

• Polymorphisms IL-1B-511IL-1B-511 and IL-1B+3954IL-1B+3954 increase the risk of gastric cancer, if the individual is homozygous. If the individual have only one allele, these polymorphisms have a protective effect.


27

Gantt Gantt ChartChartWeb siteWeb site


28


29

ReferencesReferences

http://esynopsis.uchc.edu/eAtlas/Images/GI/7278b.gif http://familydoctor.org/817.xml

http://health.gov.mt/ministry/dhi/publications/mncr/stomach.htm

http://images.google.pt

http://info.cancerresearchuk.org http://medlib.med.utah.edu/WebPath/jpeg4/GI139.jpg http://www.cancer.gov/cancerinfo/wyntk/stomach http://www.emedicine.com/med/images/1531BARRET.JPG http://www.fmed.ulaval.cag http://www.geocities.com/sampyroy2002/gd3.jpg http://www.murrasaca.com/canceres3.jpg http://www.nlm.nih.gov/ http://www.nlm.nih.gov/medlineplus/stomachcancer.html http://www.wrongdiagnosis.com/s/stomach_cancer/stats.htm

On-line On-line researchresearch

Aviva Petrie, Caroline Sabim. Medical statistics at a Glance.2005 Blackwell Science

Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003

Designing Clinical Research, 2nd ed. – Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Lippincott Williams & Wilkins. 2001.

Pai M, McCulloch M, Gorman J, Pai N, Enanoria W, Kennedy G, Tharyan P, Colford J. Systematic reviews and meta-analyses: Ana illustrated, step-by-step guide. Nat Med J India 2004;17:86-95


30

References[1] Pereira C., et al.,765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia, World J Gastroenterol, 2006 Sep 14.12(34): p. 5473-8

[2] Starzynska T., et al., The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population, Am J Gastroenterol, 2006 Feb. 101(2): p. 248-54

[3] Hellmig S., et al., A functional promotor polymorphism of TNF-alpha is associated with primary gastric B-Cell lymphoma, Am J Gastroenterol, 2005 Dec. 100(12): p. 2644-9

[4] Palli D., et al., Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population, Am J Gastroenterol, 2005 Sep. 100(9): p. 1941-8

[5] Perri F., et al., Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence, Cytokine, 2005 Jun 7. 30(5): p. 293-302

[6] Hartland S., et al., A functional polymorphism in the interleukin-1 receptor-1 gene is associated with increased risk of Helicobacter pylori infection but not with gastric cancer, Dig Dis Sci, 2004 Sep. 49(9): p. 1545-50

[7] Figueiredo C., et al., Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma, J Natl Cancer Inst, 2002 Nov 20. 94(22): p.1680-7

[8] Machado JC., et al., Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma, Gastroenterology, 2001 Oct.121(4): p. 823-9

[9] Ikehara SK., et al., A polymorphism of C-to-T substitution at -31 IL1B is associated with the risk of advanced gastric adenocarcinoma in a Japanese population, J Hum Genet, 2006. 51(11): p. 927-33

[10] Zhang WH., et al., Association of interleukin-1B (IL-1B) gene polymorphisms with risk of gastric cancer in Chinese population, Cytokine, 2005 Jun 21. 30(6): p. 378-81

[11] Lu W., et al., Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population, Carcinogenesis, 2005 Mar. 26(3): p. 631-6

[12] Chang YW., et al., Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer, Int J Cancer, 2005 Apr 10. 114(3): p. 465-71

[13] Zeng ZR., et al., Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China, Gut, 2003 Dec. 52(12): p. 1684-9

[14] El-Omar EM., et al., Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms, Gastroenterology, 2003 May. 124(5): p. 1193-201

[15] El-Omar EM., et al., Interleukin-1 polymorphisms associated with increased risk of gastric cancer, Nature, 2000 Mar 23. 404(6776): p.398-402


31

The EndThe End

Documents

Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review Authors: Catarino, Rosa; Costa, Flávio; Félix, Joana; Leal, Nuno; Mendes, Leonor;